Pim kinases are family of three highly-related serine and threonine protein kinases encoded by the genes Pim-1, Pim-2, and Pim-3. The gene names are derived from seminal experiments by Anton Berns et al., seeking oncogenes causing lymphoma, and the names are derived from the phrase Proviral Insertion, Moloney, as they were discovered as frequent integration sites for murine moloney virus wherein the insertions lead to overexpression of Pim's and either de novo T-cell lymphomas, or dramatic acceleration of tumorigenesis in a transgenic Myc-driven lymphoma model, revealing not only a strong synergy with the oncogene c-Myc, but also a functional redundancy among Pim kinase family members and suggesting that inhibition of the Pim's may have therapeutic benefit. (Cuypers et al (1984) Cell vol. 37 (1) pp. 141-50; Selten et al (1985) EMBO J vol. 4 (7) pp. 1793-8; van der Lugt et al (1995) EMBO J vol. 14 (11) pp. 2536-44; Mikkers et al (2002) Nature Genetics vol. 32 (1) pp. 153-9; van Lohuizen et al (1991) Cell vol. 65 (5) pp. 737-52).
Mouse genetics suggest that antagonizing Pim kinases should have an acceptable safety profile; a Pim 1−/−; Pim-2−/−, Pim-3−/− mouse knockout is viable although slightly smaller than wild type littermates (Mikkers et al (2004) Mol Cell Biol vol. 24 (13) pp. 6104-154). The three genes give rise to six protein isoforms that are little more than a protein kinase domain. In particular, they are without recognizable regulatory domains. All six isoforms are constitutively active protein kinases that do not require post-translational modification for activity, thus Pim kinases are regulated primarily at the transcriptional level (Qian et al (2005) J Biol Chem vol. 280 (7) pp. 6130-7). Pim kinase expression is highly inducible by cytokines and growth factors receptors and Pim's are direct transcriptional targets of the Stat proteins, including Stat3 and Stat5. Pim-1, for example, is required for the gp130-mediated Stat3 proliferation signal (Aksoy et al (2007) Stem Cells vol. 25 (12) pp. 2996-3004; Hirano et al (2000) Oncogene vol. 19 (21) pp. 2548-56; Shirogane et al (1999) Immunity vol. 11 (6) pp. 709-19).
Pim kinases have been shown to function in cellular proliferation and survival pathways parallel to the PI3K/Akt/mTOR signaling axis (Hammerman et al (2005) Blood vol. 105 (11) pp. 4477-83). Indeed, several of the phosphorylation targets of the PI3k axis including Bad and eIF4E-BP1 are cell growth and apoptosis regulators and are also phosphorylation targets of the Pim kinases (Fox et al (2003) Genes Dev vol. 17 (15) pp. 1841-54; Macdonald et al (2006) Cell Biol vol. 7 pp. 1). Pim-1 kinase promotes inactivation of the pro-apoptotic Bad protein by phosphorylating it on the Ser112 gatekeeper site, suggesting a role for the Pim kinase in cell survival since phosphorylation of Bad increases Bcl-2 activity and therefore promotes cell survival (Aho et al BMC FEBS Letters (2004) vol. 571 (1-3) pp. 43-9; Tamburini et al (2009) Blood vol. 114 (8) pp. 1618-27). Likewise, phosphorylation of eIF4E-BP1 by mTOR or Pim kinases causes depression of eIF4E, promoting mRNA translation and cellular growth. In addition, Pim-1 has been recognized to promote cell cycle progression through phosphorylation of CDC25A, p21, and Cdc25C (Mochizuki et al (1999) J Biol Chem vol. 274 (26) pp. 18659-66; Bachmann et al (2006) Int J Biochem Cell Biol vol. 38 (3) pp. 430-43; Wang et al (2002) Biochim Biophys Acta vol. 1593 (1) pp. 45-55).
Pim kinases have been implicated in multiple human oncology indications. Pim kinases show strong synergy in transgenic mouse models with c-Myc-driven and Akt-driven tumors (Verbeek et al (1991) Mol Cell Biol vol. 11 (2) pp. 1176-9; Allen et al (1997) Oncogene vol. 15 (10) pp. 1133-41; Hammerman et al (2005) Blood vol. 105 (11) pp. 4477-83). Pim Kinases are required for the transforming activity of oncogenes identified in acute myeloid leukemia (AML) including Flt3-ITD, BCR-ab1, and Tel-Jak2. Expression of these oncogenes in BaF3 cells results in strong upregulation of Pim-1 and Pim-2 expression, resulting in IL-3 independent growth, and subsequent pim inhibition results in apoptosis and cell growth arrest (Adam et al (2006) Cancer Research vol. 66 (7) pp. 3828-35). Pim overexpression and dysregulation has also been noted as a frequent event in many hematopoetic cancers, including leukemias and lymphoma (Amson et al (1989) Proc Natl Acad Sci USA vol. 86 (22) pp. 8857-61); Cohen et al (2004) Leuk Lymphoma vol. 45 (5) pp. 951-5; Hüttmann et al (2006) Leukemia vol. 20 (10) pp. 1774-82), as well as multiple myeloma (Claudio et al (2002) Blood vol. 100 (6) pp. 2175-86).
In prostate cancer, Pim-1 has been shown to be overexpressed and correlated to disease progression (Cibull et al (2006) J Clin Pathol vol. 59 (3) pp. 285-8; Dhanasekaran et al (2001) Nature vol. 412 (6849) pp. 822-6). Pim 1 expression increases with disease progression in mouse models of prostate cancer progression (Kim et al (2002) Proc Natl Acad Sci USA vol. 99 (5) pp. 2884-9). Pim-1 has been reported to be the most highly overexpressed mRNA in the subset of human prostate tumor samples which have a c-Myc-driven gene signature (Ellwood-Yen et al (2003) Cancer Cell vol. 4 (3) pp. 223-38). Pim-3 has been also been shown to be overexpressed and to have a functional role in pancreatic cancer and Hepatocellular Carcinoma (Li et al. (2006) Cancer Research vol. 66 (13) pp. 6741-7; Fujii et al (2005) Int J Cancer vol. 114 (2) pp. 209-18).
Therefore, multiple lines of evidence exist to support the possible therapeutic value of Pim kinase inhibition in oncology. Beyond these applications, Pim kinases could play an important role in normal immune system function and Pim inhibition could be therapeutic for a number of different immunologic pathologies including inflammation, autoimmune conditions, allergy, and immune suppression for organ transplantation (Aho et al (2005) Immunology vol. 116 (1) pp. 82-8).